Description: (Modified from Applicant's Abstract) Sensory information including pain is conveyed to the CNS through primary afferent fibers and transmitted synaptically by the release of glutamate and neuropeptides from the central terminals of primary afferent fibers. The ATP P2x receptor is a new family of ligand-gated cation channels for which extracellular ATP is the endogenous ligand. We have found that P2x receptors are localized at presynaptic terminals on cultured DRG neurons. Activation of these receptors not only enhances spontaneous glutamate release, but surprisingly, it directly elicits action potentials at DRG presynaptic terminals, triggering synchronous multiquantal glutamate release. Studies proposed here will test two central hypotheses: 1) Presynaptic P2x receptors act as a 'central sensory signal generator' to directly initiate sensory signals at the central terminals of afferent fibers. 2) P2x receptor activation enhances glutamate release evoked by conventional sensory impulses. In addition, we will also examine whether endogenous ATP is release from DRG presynaptic terminals. Electrophysiological, pharmacological and immunocytochemical approaches will be applied and experiments will be conducted on a spinal cord slice preparation and a DRG-dorsal horn culture system. The proposed P2x receptor functions will be examined on the primary afferents that are potentially nociceptive types. The long-term objective of our studies are to explore the roles of P2x receptors in both centrally generated pathological pain and in sensory hypersensitivity such as hyperalgesia.